USPTO Patents Application 09993647

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization

International Bureau

(43) International Publication Date
18 January 2001 (18.01.2001)

PCT

lillllllllllllllllllllililli

(10) International Publication Number

WO 01/04115 A2

(51) International Patent Classification^: C07D 413/00

(21) International Application Number: PCT/USOO/17655

(74) Agents; RAYMOND, Robert et al.; Boehringer Ingel-
heim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box
368, Ridgefield, CT 06877 (US).

(22) International Filing Date: 27 June 2000 (27.06.2000) Designated States (national): OA, JP, MX.

(25) Filing Language:

(26) Publication Language:

(30) Priority Data:

60/143,094

English

English

9 July 1999 (09.07.1999) US

(71) Applicant: BOEHRINGER INGELHEIM PHAR-
MACEUTICALS, INC. [US/US]; 900 Ridgebury Road,
Ridgefield, CT 06877 (US).

(72) Inventors: ZHANG, Lin-Hua; 90 Gillotti Road, New
Fairfield, CT 06812 (US). ZHU, Lei; 80 Secor Lane,
Hopewell Junction, NY 12533 (US).

(84) Designated States (regional): European patent (AT, BE,
CH, CY, DE, DK, ES, FX, FR, GB, GR, IE, IT, LU, MC,
NL, PT, SE).

Published:

— Without international search report and to be republished
upon receipt of that report.

For two-letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations" appearing at the begin-
ning of each regular issue of the PCT Gazette.

(54) Title: NOVEL PROCESS FOR SYNTHESIS OF HETEROARYL-SUBSTITUTED UREA COMPOUNDS

(57) Abstract: Disclosed are novel processes and novel intermediate compounds for preparing aryl- and heteroaryi-substituted urea
compounds of formula (I) wherein Ari, Ari, L, Q and X are described herein. The product compounds are useful in pharmaceutic
compositions for treating diseases or pathological conditions involving inflammation such as chronic inflammatory diseases.

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Novel Process for Synthesis of Heteroaryl-substituted Urea Compounds

RRLATED APPLICATION DATA

This application claims benefit to US Provisional Application Serial No. 60/143,094,
filed July 9, 1999.

TECHNICAL FIELD OF THE INVENTION

10

This invention relates to novel processes for preparing new aryl-and heteroaryl-
substituted urea compounds of formula (I):

wherein Ari, Ar2, X, L and Q are defined below, which are useful for treating diseases
and pathological conditions involving inflammation such as chronic inflammatory
disease.

20

BACKGROUND OF THE INVENTION

Aryl- and heteroaryl-substituted ureas have been described as inhibitors of cytokine
production. Examples of such compounds are reported in WO 99/23091 and in WO
25 98/52558. These inhibitors are described as effective therapeutics in cytokine-mediated
diseases, including inflammatory and autoimmune diseases.

A key step in the synthesis of these compounds is the formation of the urea bond.
Various methods have been reported to accomplish this. For example, as reported in the

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above references, an aromatic or heteroaromatic amine, II, may be reacted with an
aromatic or heteroaromatic isocyanate III to generate the urea IV (Scheme I)

Scheme I

Ar

^ NH2 +

Ar

2\

NCO

Ar

N
H

O

N
H

Ar

III

IV

If not commercially available, one may prepare the isocyanate III by reaction of an aryl
or heteroaryl amine Ar2NH2 with phosgene or a phosgene equivalent, such as

10 bis(trichloromethyl) carbonate (triphosgene) (P. Majer and R. S. Randad, J. Org. Chem.
1994, 59, 1937) or trichloromethyl chloroformate (diphosgene). K. Kurita, T. Matsumura
and Y. Iwakura, J. Org. Chem. 1976, 41, 2070) to form the isocyanate III, followed by
reaction with AriNHa to provide the urea. Other approaches to forming the urea known
in the chemical literature are to form a carbamate, as shown in Scheme II below, by

15 reaction of an amine with a chloroformate derivative, such as phenyl chloroformate (B.
Thavonekham, Synthesis, 1997, 1 189), chloromethyl chloroformate (T. Patonay, E.
Patonay-Peli, L Zolnai and F. Mogyorodi, Synthetic Communications, 1996, 26, 4253),
p-nitrophenyl chloroformate (J. Gante, Chem. Ber. 1965, 98, 3334), or 2,4,5-
trichlorophenyl chloroformate (A. W. Lipkowski, S. W. Tam and P. S. Portoghese, J.

20 Med. Chem. 1986, 29, 1222) to form a carbamate V. This may then be reacted with an
aryl or heteroaryl amine (II) to provide urea IV (Scheme II- reaction with phenyl
chloroformate shown). The synthesis of ureas through (phenoxycarbonyl)tetrazole (R.
W. Adamiak, J. Stawinski, Tetrahedron Lett. 1977, 1935) or 1,1'-
carbonylbisbenzotriazole (A. R. Katritzky, D. P. M. Pleynet and B. Yang, J. Org. Chem.

25 1997, 62, 4155) has been reported. In addition, preparation of ureas by catalytic

carbonation of amines with carbon monoxide or carbon dioxide has been documented in
the literature (N. Sonoda, T. Yasuhara, K. Kondo, T. Ikeda and S. Tsutsumi, J. Am.
Chem. Soc. 1971, 93, 691; Y. Morimoto, Y. Fujiwara, H. Taniguchi, Y. Hori and Y.

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Nagano, Tetrahedron Lett. 1986, 27, 1809). In each of these cases, Ari and Ax2 may be
modified before and/or after the urea formation to produce desired compounds.

Scheme II

V IV

Each of the methods described above suffer from one or more disadvantages. For
10 example, phosgene and phosgene equivalents are hazardous and dangerous to use,

particularly in large-scale applications. In addition the isocyanate intermediate III is not
stable and may undergo decomposition during preparation and storage. The urea
formation may be done using a phenyl carbamate, as illustrated in Scheme II and U.S.
Application Serial No. 09/484,638. However, the by-product phenol formed in the urea
15 synthesis does not have sufficient water solubility to be easily removed by water washing
especially at large scale. Thus it may require multiple washing and several
crystallizations to obtain highly pure product. For these reasons these methods are not
well-suited for industrial-scale production.

20 U.S. Application Serial No. 09/484,638 also discloses the synthesis of substituted
naphthyl amino intermediates for use in making aryl-and heteroaryl-substituted urea
compounds of the formula(I) as described therein. This synthesis begins with 4-
aminonapthol which is protected with a Boc (/er^-butoxycarbonyl) group on the amine

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prior to alkylation and deprotection. This procedure is also not amenable to industrial-
scale production. The starting 4-aminonaphthol is very expensive and not available in
large quantity. In addition the protection and deprotection steps are tedious and add to
the expense.

Disclosed herein are novel processes for making the aryl-and heteroaryl-substituted urea
compounds of the formula(I) including those disclosed in U.S. Application Serial No.
09/484,638 and novel intermediates useful in such processes.

It is therefore an object of this invention to provide a general and cost-effective process
for the preparation of the aryl- and heteroaryl-substituted urea compounds of the
formula(I) shown below^:

comprising the steps of:

reacting of intermediate of formula (II) with intermediate of formula (IV) to
produce the product compound of formula (I):

BRIEF SUMMARY OF THE INVENTION

(I)

X

+

(II)

(IV)

(I)

wherein Ari, Ar2, L, Q, X and Ra are as described below.

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In addition, this invention provides efficient methods for preparing intermediates used in
the preparation of preferred cytokine-inhibiting aryl-and heteroaryl-substituted ureas.
These processes are especially well-suited for preparation of these compounds on an
5 industrial scale.

DETAILED DESCRIPTION OF THE INVENTION

10

The present invention is directed to the synthesis of compounds having formula

(I):

X

I I
H H

15 (I)

wherein:

Ari is a heterocyclic group selected from the group consisting of phenyl, pyridine,
pyridone, pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and
20 thiophene; wherein Ari is optionally substituted by one or more Rj, R2 or R3;

Ar2 is:

phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline,
25 tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being
optionally substituted with one to three R2 groups;

L, a linJcing group, is:
30 Ci-10 saturated or unsaturated branched or unbranched carbon chain;

wherein one or more methylene groups are optionally independently replaced by
0,N or S; and

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wherein said linking group is optionally substituted with 0-2 oxo groups and one
or more branched or unbranched alkyl optionally substituted by one or more halogen
atoms;

or L is a cyclic group which is:
5 a) a C5-8 cycloalkyl or cycloalkenyl optionally substituted with 1-2 0x0 groups, 1-3 Ci_4
branched or unbranched alkyl, C1.4 alkoxy or C 1-4 alkylamino chains;
b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine, pyrimidine, pyridinone,
dihydropyridinone, maleimide, dihydromaleimide, piperdine, piperazine or pyrazine each
being optionally independently substituted with 1-3 C1-4 branched or unbranched alkyl,
10 Ci.4alkoxy, hydroxy, cyano, mono- or di-(Ci_3 alkyl)amino, Ci_6 alkyl-S(0)q, or halogen;

wherein said cyclic group is optionally attached to a Ci^ saturated or unsaturated
branched or unbranched carbon chain wherein said carbon chain is in turn covalently
attached to Q , said carbon chain is optionally partially or fully halogenated and wherein
one or more methylene groups are optionally replaced by O, NH, S(0), S(0)2 or S,
15 wherein said methylene groups are further optionally independently substituted with 1-2
0x0 groups and one or more C1.4 branched or unbranched alkyl optionally substituted by
one or more halogen atoms;

20 Q is selected from the group consisting of:

a) phenyl, naphthyl, pyridine, pyrimidine, pyridazine, imidazole, benzimidazole, furan,
thiophene, pyran, naphthyridine, oxazo[4,5-Z?]pyridine and imidazo[4,5-6]pyridine,
which are optionally substituted with one to three groups selected from the group

25 consisting of halogen, Ci_6 alkyl, Ci_6 alkoxy, hydroxy, mono- or di-(Ci.3 alkyl)amino,

Ci-6 alkyl-S(0)m and phenylamino wherein the phenyl ring is optionally substituted
with one to two groups selected from the group consisting of halogen, Ci_6 alkyl and
C1.6 alkoxy;

b) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxane,
30 morpholine, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone,

piperidine, piperidinone, tetrahydropyrimidone, cyclohexanone, cyclohexanol,

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pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone,
tetramethylene sulfide, tetramethylene sulfoxide and tetramethylene sulfone which
are optionally substituted with one to three groups selected from the group consisting
of Ci.6 alkyl, C\.6 alkoxy, hydroxy, mono- or di-(Ci.3 alky l)amino-C 1.3 alkyl,
5 phenylamino-Ci-3 alkyl and C1-3 alkoxy-Ci_3 alkyl;

c) Ci-6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently
bonded to groups selected from the group consisting of C 1-3 alkyl and C1.5 alkoxy alkyl
and phenyl wherein the phenyl ring is optionally substituted with one to two groups
selected from the group consisting of halogen, Ci_6 alkoxy, hydroxy or mono- or di-
10 (Cu3 alkyl)amino, Ci_6 alkyl-S(0)r and phenyl-S(0)t, wherein the phenyl ring is

optionally substituted with one to two groups consisting of halogen, C1.6 alkoxy,
hydroxy and mono- or di-(Ci.3 alkyl)amino;

Ri is selected from the group consisting of:

15

(a) C3_io branched or unbranched alkyl, which may optionally be partially or fully
halogenated, and optionally substituted with one to three phenyl, naphthyl or
heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl,
pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and

20 isothiazolyl; each such phenyl, naphthyl or heterocycle selected from the group

hereinabove described, being substituted with 0 to 5 groups selected from the group
consisting of halogen, C\.6 branched or unbranched alkyl which is optionally partially
or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, cyano, C1.3 alkyloxy
which is optionally partially or fully halogenated, NH2C(0) and

25 di(Ci.3)alkylaminocarbonyl;

(b) C3-7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl,
cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and
bicycloheptanyl, which are optionally partially or fully halogenated and optionally
substituted with one to three C1.3 alkyl groups, or an analog of such cycloalkyl group

30 wherein one to three ring methylene groups are replaced by groups independently

selected from O, S, CHOH, >C=0, >C=S and NH;

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(c) C3-10 branched alkenyl optionally partially or fully halogenated, and optionally
substituted with one to three C1.5 branched or unbranched alkyl, phenyl, naphthyl or
heterocyclic groups, with each such heterocyclic group being independently selected
from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,
imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such
phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected
from halogen, Ci_6 branched or unbranched alkyl which is optionally partially or fully
halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, cyano, Ci_3 alkyloxy
which is optionally partially or fully halogenated, NH2C(0) and mono- or di(Ci-
3)alkylaminocarbonyl;

(d) C5-7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl,
cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and
bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one
to three C1.3 alkyl groups;

(e) cyano; and,

(f) methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;

R2 is selected from the group consisting of:

a Ci-6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl,
aroyl, C1-4 branched or unbranched alkoxy optionally partially or fully halogenated,
halogen, methoxycarbonyl and phenylsulfonyl;

R3 is selected from the group consisting of:

a) a phenyl, naphthyl or heterocyclic group selected from the group consisting of
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl,
thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl,
indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl,

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benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl,
quinoxalinyl, quinazolinyl, purinyl and indazolyl wherein such phenyl, naphthyl or
heterocyclic group is optionally substituted with one to five groups selected from the
group consisting of a Ci_6 branched or unbranched alkyl, phenyl, naphthyl,
5 heterocycle selected from the group hereinabove described, Ci-6 branched or

unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl,
cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,
bicyclohexanyl, bicycloheptanyl, phenyl C1.5 alkyl, naphthyl Ci_5 alkyl, halo, hydroxy,
cyano, C1-3 alkyloxy which may optionally be partially or fully halogenated,

10 phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected

from the group hereinabove described, nitro, amino, mono- or di-(Ci.3)alkylamino,
phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is
selected from the group hereinabove described, NH2C(0), a mono- or di-(Ci.3)alkyl
aminocarbonyl, C1-5 alkyl-C(0)-Ci_4 alkyl, amino-Ci.5 alkyl, mono- or di-(Ci-

15 3)alkylamino-Ci-5 alkyl, amino-S(0)2, di-(Ci-3)alkylamino-S(0)2, R4-C1.5 alkyl, R5-C1-

salkoxy, R6-C(0)-Ci-5 alkyl and R7-C1-5 alkyl-NCRg)-;
b) a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl,
indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and
benzocycloheptenyl, or a fused heterocyclyl selected from cyclopentenopyridine,

20 cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine,

cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine,
cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline,
cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole,
cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole,

25 cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole,

cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein
the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups
independently selected from phenyl, naphthyl, heterocyclyl selected from the group
consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,

30 pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, Ci-6 branched or unbranched

alkyl which is optionally partially or fully halogenated, halo, cyano, Ci_3 alkyloxy

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which is optionally partially or fully halogenated, phenyloxy, naphthyloxy,
heterocyclyloxy wherein the heterocyclyl moiety is selected from the group
hereinabove described, nitro, amino, mono- or di-(Ci-3)alkylamino, phenylamino,
naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from
the group hereinabove described, NH2C(0), a mono- or di-(Ci.3)alkyl aminocarbonyl,
Ci_4 alkyl-OC(O), Ci_5 alkyl-C(0)-Ci.4 branched or unbranched alkyl, an amino-Ci.5
alkyl, mono- or di-(Ci.3)alkylamino-Ci.5 alkyl, R9-C1.5 alkyl, Rio-Ci_5 alkoxy, Rn-
C(0)-Ci.5 alkyl and R12-C1.5 alkyl-N(Ri3)-;

c) cycloalkyl selected from the group consisting of cyclopentanyl, cyclohexanyl,
cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, wherein the
cycloalkyl is optionally partially or fully halogenated and optionally substituted with
one to three C1.3 alkyl groups;

d) C5.7 cycloalkenyl, selected from the group consisting of cyclopentenyl, cyclohexenyl,
cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and
bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one
to three Ci_3 alkyl groups;

e) acetyl, aroyl, alkoxycarbonylalkyl and phenylsulfonyl; and

f) C1.6 branched or unbranched alkyl optionally partially or fully halogenated;
Ri and R2 taken together optionally form a fused phenyl or pyridinyl ring;

each Rg or R13 is independently selected from the group consisting of:

hydrogen and Ci^ branched or unbranched alkyl optionally partially or fully halogenated;

each R4, R5, R6j R7, R95 Rio? Rii and R12 is independently selected from the group
consisting of:

morpholine, piperidine, piperazine, imidazole and tetrazole;

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m is 0, 1 or 2;
q is 0, 1 or 2;

5

r is 0, 1 or 2;

t is 0, 1 or 2; and

10 Xis OorS.

The compounds of the invention may be prepared as physiologically and
pharmaceutically acceptable salts, as may seem appropriate to one of ordinary skill in the
art.

15

The compounds produced by the novel process of the invention are only those which are
contemplated to be 'chemically stable' as v^ill be appreciated by those skilled in the art.
For example, a compound which would have a 'dangling valency', or a 'carbanion' are
not compounds contemplated to be made by the novel process.

20

All terms as used herein in this specification, unless otherwise stated, shall be understood
in their ordinary meaning as known in the art. For example, "Ci_4alkoxy" is a Ci_4alkyl
with a terminal oxygen, such as methoxy, ethoxy, propoxy, pentoxy and hexoxy. All
alkyl, alkenyl and alkynyl groups shall be understood as being branched or unbranched
25 where structurally possible and unless otherwise specified. Other more specific
definitions are as follows:

The term "aroyl" as used in the present specification shall be understood to mean
"benzoyl" or "naphthoyl".
30 NMP: l-methyl-2-pyrrolidinone;
THF: tetrahydrofuran;

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DMF: N,N' -dimethyl formamide;
DMAC: N-N'-dimethylacetamide;
DMSO: dimethylsulfoxide;
DMAP: 4-dimethylaminopyridine;
5 DBU: l,8-diazabicyclo[5.4.0]undec-7-ene;

PROCESS FOR MAKING COMPOUNDS OF THE FORMULAri;^

Reacting in a suitable solvent an amino-heterocycle NHa-Ari with a haloformate
15 RaOC(X)Ha, wherein Ra represents C2-3 halocarbon, preferably 2,2,2-trichloroethyl, and
Ha represents halogen, preferably chloro, X is as defined above, in the presence of a
suitable base, to produce carbamate of the formula (II):

Preferable formate RaOC(X)Ha are those, which upon hydrolysis of the formula(II)
intermediates, will form a water soluble byproduct which is easily removed by aqueous
25 washing, such byproduct would be, for example, 2,2,2-trichloroethanol. Examples of

preferred RaOCOHa are trichloroethyl chloroformate or trichloroethyl chlorothioformate.
Accordingly, a preferred compound of the formula(II) is:

10 The novel process comprises:

STEP 1:

H

20

(II)

X

OCH2CCI3

30

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Synthesis of amino-heterocycle NH2-Ari has been illustrated in US Patent Application
No. 09/484,638, incorporated herein by reference. A particularly preferred compound of
the formula(II) is where Ari is l-tolyl-3-/-butyl-pyrazole-5-yl.

5 Reaction conditions such as the selection of a suitable solvent and temperature is within
the skill of the ordinary artisan depending on the particular compounds desired.
Typically, the reaction of stepl is in a non-aqueous or an aqueous solvent, preferably
THF or ethyl acetate, in the presence of a suitable base such as tertiary amine for example
triethylamine, diisopropylethylamine, N-methylpyrrolidine, DBU(1,8-

10 diazabicyclo[5.4.0]undec-7-ene), DMAP(4-dimethylaminopyridine), N-

methylmorpholine, pyridine, methyl pyridine or inorganic bases such as sodium
hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium
carbonate and potassium bicarbonate. Preferred suitable bases for step 1 are
diisopropylethylamine, NaOH or N-methylpyrrolidine. The reaction occurs at a

15 temperature of about 0 - lOC'C, preferably 5 - 15 °C, for about 0.5 - 24 hrs, preferably 3-
4 hrs.

20 For certain preferred embodiments, Step 2 proceeds as follows. Reacting a Z-Ar2-MH,
where Z is a nitro or nitroso group, M is O, S, or NH, and Ar2 is as defined hereinabove,
with a Y-J-Q moiety in a suitable solvent to produce the intermediate of formula (III)

wherein L and Q are as defined hereinabove , Y is a leaving group such as a halogen and
M-J constitutes L;

STEP 2

25

(III)

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A suitable solvent for the above reaction would be a polar non-protic organic solvent,
such as acetonitrile, DMF (N,N'-dimethylformamide), DMAC (N-N'-
dimethylacetamide), DMSO (dimethylsulfoxide) and NMP (l-methyl-2-pyrrolidinone),
preferably NMP, at a temperature of about 50 - 100 preferably between 75 - 95 ^C,
5 for about 0.5-24 hrs, preferably 3-4 hrs.

For other embodiments of L, analogous methods can be found in U.S. Patent Application
Nos. 09/484,638 and 09/505,582 incorporated in their entirety by reference.

10 STEP 3

Reducing compound of formula (III) with catalytic hydrogenation or non-catalytic
reduction to produce the intermediate of formula (IV):

Catalytic hydrogenation is preferred, a preferred catalyst is Pd/C. Reaction conditions
20 such as the selection of a suitable solvent and temperature is within the skill of the

ordinary artisan. The catalytic hydrogenation with respect to H2 pressure and time can be
varied, a preferable hydrogenation occurs under about 30 psi for about 1 hr - 24 hours.

25 Reacting the intermediate of formula (II) with the intermediate of formula (IV) with or
without base, preferably with a base. A suitable base will be one such as tertiary amine
for example triethylamine, diisopropylethylamine, N-methylpyrrolidine, DBU, DMAP,
N-methylmorpholine, pyridine, methyl pyridine or an inorganic base such as sodium
hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium

30 carbonate and potassium bicarbonate. Preferred bases are diisopropylethylamine or N-

15

2

(IV)

STEP 4

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methylpyrrolidine. The reaction takes place in the presence of suitable solvent to produce
the product of formula (I):

Reaction conditions such as the selection of a suitable solvent, base and temperature can
be varied according to the specific compound of the formula(I) that is desired. The
reaction can be run in a suitable polar, or a suitable non-polar solvent such as methylene

10 chloride or chloroform or in heptane, hexane, cyclohexane, ethyl acetate, benzene,

toluene, xylene, tetrahydropfuran, dioxane, ethyl ether, methyl butyl ether or in a biphasic
aqueous/organic mixture. Preferably the solvent will be a polar non-protic organic solvent
such as NMP(l-methyl-2-pyrrolidinone), acetonitrile, DMF(N,N-dimethylformamide),
DMAC(N,N-dimethylacetamide) or DMSO, more preferably DMSO or NMP, which is

15 heated to an appropriate temperature, preferably about 55-60 °C for about 1 .5 hours.
Particular separation methods depending on the compound desired will be apparent to
those of ordinary skill in the art, A preferred method is shown in Example 1 in the present
specification.

20 A preferred subgeneric aspect of the invention comprises a process of producing

compounds of the formula(I) wherein Ar2 is naphthyl, tetrahydronaphthyl, indanyl or
indenyL

A more preferred subgeneric aspect of the invention comprises a process of producing
25 compounds of the formula(I) wherein Ar2 is naphthyl.

A yet more preferred subgeneric aspect of the invention comprises a process of producing
compounds of the formula (I), as described in the immediate previous paragraph,
wherein:

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Ari is thiophene or pyrazole;
Ar2 is 1-naphthyl;

L is Ci_6 saturated or unsaturated branched or unbranched carbon chain wherein
one or more methylene groups are optionally independently replaced by
5 0,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups
and one or more C1-4 branched or unbranched alkyl optionally substituted by one or more
halogen atoms;

or L is cyclopentenyl, cyclohexenyl, cycloheptenyl, each optionally substituted with an
0x0 group or 1-3 C1-4 branched or unbranched alkyl, Ci^alkoxy or Ci^alkylamino; or L

10 is phenyl, pyridine, furan or thiophene each being optionally independently substituted
with 1-3 Ci_4 branched or unbranched alkyl, Ci.4alkoxy, hydroxy, cyano, mono- or di-
(C1.3 alkyl)amino. Cue alkyl-S(0)q or halogen;

wherein said cyclic group is optionally attached to a C1.4 saturated or unsaturated
branched or unbranched carbon chain wherein said carbon chain is in turn covalently

15 attached to Q , said carbon chain is optionally partially or fully halogenated and wherein
one or more methylene groups are optionally replaced by O, NH, S(0), S(0)2 or S,
wherein said methylene groups are further optionally independently substituted with 1-2
0x0 groups and one or more Ci_4 branched or unbranched alkyl optionally substituted by
one or more halogen atoms;

20

Ri is C3.4alkyl branched or unbranched, cyclopropyl or cyclohexanyl optionally
partially or fully halogenated and optionally substituted with one to three C1.3 alkyl
groups;

R3 is selected from the group consisting of Ci-4alkyl branched or unbranched
25 optionally partially or fully halogenated, cyclopentanyl optionally partially or fully
halogenated and optionally substituted with one to three C1-3 alkyl groups,

phenyl, pyridinyl each being optionally substituted with one to five groups
selected from the group consisting of a C1.6 branched or unbranched alkyl, phenyl,
naphthyl, pyridinyl, Cue branched or unbranched alkyl which is optionally partially or
30 fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1.5 alkyl, naphthyl C1.5 alkyl,

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halo, hydroxy, cyano, Ci_3 alkyloxy which may optionally be partially or fully
halogenated, phenyloxy, naphthyloxy, pyridinyloxy, nitro, amino, mono- or di-(Ci,
3)alkylamino, phenylamino, naphthylamino, pyridinylamino, NH2C(0), a mono- or di-
(Ci.3)alkyl aminocarbonyl, Ci_5 alky 1-C(0)-C 1.4 alkyl, amino-Ci-5 alkyl, mono- or di-(Ci_
5 3)alkylamino-Ci-5 alkyl, amino-S(0)2, di-(Ci.3)alkylamino-S(0)2, R4-Ci.5alkyl, Rs-Ci-s
alkoxy, R6-C(0)-Ci.5 alkyl and R7-C1-5 alkyl-N(R8)-; and R3 is alkoxycarbony lalkyl ;

A yet further preferred subgeneric aspect of the invention comprises a process of
producing compounds of the formula (I), as described in the immediate previous
10 paragraph, wherein Ari is pyrazole.

A still yet further preferred subgeneric aspect of the invention comprises a process of
producing compounds of the formula (I), as described in the immediate previous
paragraph, wherein L is C1.5 saturated carbon chain wherein one or more methylene
15 groups are optionally independently replaced by 0,N or S; and wherein said linking
group is optionally substituted with 0-2 0x0 groups and one or more Ci^ branched or
unbranched alkyl optionally substituted by one or more halogen atoms;

More particularly preferred embodiments of the process of the invention is where L is
20 propoxy, ethoxy, methoxy, methyl, propyl, C3-5 acetylene or methylamino each being
optionally substituted as described herein and Q is morpholine.

A even more particularly preferred embodiment of L is ethoxy optionally substituted, the
base is diisopropylethylamine and the polar non-protic organic solvent is DMSO.

25

In order that this invention be more fully understood, the following examples are set
forth. These examples are for the purpose of illustrating preferred embodiments of this
invention, and are not to be construed as limiting the scope of the invention in any way.

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SYNTHETIC EXAMPLES
EXAMPLE 1

l-[3-tert'butyl'l'p-tolyl'lH'pyrazol-5'yl]-3-[4-(2'morpholin'4-^^
ylj'urea.

(I)

5-Ainino-3-r-butyl-l-/7-tolylpyrazole hydrochloride: A solution of pivaloylacetonitrile
(750 g, 6.0 mol) and /7-tolylhydrazine hydrochloride (660 g, 4.2 mol) in methanol (2.8 L)
was refluxed for 3 h. Heptane was added, and methanol was removed by distillation.
The product was crystallized from the solution, collected by filtration and dried in
vacuum oven to constant weight. Yield: 1.05 kg, 94%. 'H NMR 5 (CDCI3) 7.50 (d, 2H),
7.30 (d, 2H), 5.60 (s, IH), 2.45 (s, 3H), 1.40 (s, 9H). MS (CI) m/z 229 (M^ + H).

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5-(2,252-Trichloroethoxycarbonyl)amino-3-^-butyl-l-/?-tolylpyrazole: A mixture of 5-
amino-3-/-butyl-l-/7-tolylpyrazole hydrochloride (300 1.13 mol), water (0.9 L), EtOAc
(2.1 L) and NaOH (1 17 g, 2.84 mol) was stirred between 5 -15 for 30 min. To this
mixture, 2,2,2-trichloroethyl chloroformate (342 g, 1.58 mol) was added over 1 h
5 between 5 - 1 5 ^C. The mixture was stirred at room temperature for 2 h, and then the
aqueous layer was separated from the EtOAc layer. The EtOAc layer was washed with
brine (2 x 0.9 L) and dried over MgS04 (60 g). The EtOAc layer was collected by
filtration. To this solution, heptane was added. A part of the solution was removed by
distillation. The product was crystallized from the solution, collected by filtration and
10 dried in vacuum oven to constant weight. Yield: 409 g, 90%. NMR (CDCI3) 5 7.40
(d, 2H), 7.30 (d, 2H), 6.40 (s, IH), 4.80 (s, 2H), 2.40 (s, 3H), 1.40 (s, 9H). MS (EI) m/z
404 (M"").

4-Nitro-l-(2-morpholinethoxy)naphthalene: A mixture of 4-nitro-l-
15 hydroxynaphthalene (194 g, 1.0 mol), 4-(2-chloroethyl)morpholine hydrochloride (264 g,
1.4 mol), NaOH (58 g, 1.4 mol), K2CO3 (339 g, 2.4 mol) and 1 -methyl-2-pyrrohdinone
(1.0 L) was heated to 90- 100 and held for 1 - 2 h. The mixture was cooled to 40
and water was slowly added. The mixture was cooled to 5 and held for 4 h. The
product was collected by filtration, washed with water, cyclohexane and dried in vacuum
20 to constant weight. Yield: 227 g, 75%. NMR (CDCI3) 5 8.76 (d, IH), 8.38 (m, 2H),
7,74 (dd, IH), 7.58 (dd, 1 H), 6.79 (d, 1 H), 4.38 (dd, 2 H), 3.74 (d, 4 H), 2.98 (dd, 2H),
2.65 (d, 4 H). MS (EI) m/z 303 (M + 1).

4-Ainino-l-(2-morpholinethoxy)naphthalene hydrochloride: A mixture of 4-nitro-l-
25 (2-morpholinethoxy)naphthalene (40 g, 0.13 mol), MeOH (280 mL) and Pd/C (50%

water, 1.2 g) was hydrogenated under 30 psi for 24 h. The catalyst was filtered through a
layer of diatomaceous earth under nitrogen. To this filtrate 20 mL of HCl (37%) and
cyclohexane (200 mL) were added. The solvent was removed under reduced pressure
and the product collected by filtration. The product was dried in vacuum to constant
30 weight. Yield: 33 g, 82%. ^H NMR (DMSO) 5 8.38 (d, IH), 8.00 (d, IH), 7.72 (dd, IH),

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7.64 (m, 2H), 7.05 (d, IH), 4.62 (s, 2H), 4.00 (b, 4H), 3.88 (s, 2H), 3.40 (b, 4H). MS (EI)
m/z 273 (M").

l-[3~tert-butyl'l-p-tolyl~lH-pyrazol-5-yl]-3~[4'(2'morpholin-4-yl-e^
5 ylj-urea: A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-r-butyl-l-p-

tolylpyrazole ( 10.6 g, 26 mmol), 4-amino-l-(2-inorpholinethoxy)naphthalene (free base
from HCl salt above, 7.16 g, 26 mmol), diisopropylethylamine (3.2 g, 25 mmol) and
DMSO (75 mL) was heated to 55 - 60 and held for 1.5 h. To this solution, ethyl
acetate (100 mL) was added. The organic layer was washed with brine (4x50 mL), and

10 dried over MgS04. The solvent was removed under reduced pressure, and residue was
crystallized from acetonitrile (50 mL) at 0 ^C. The product was collected by filtration,
recrystallized from isopropanol and dried in vacuum to constant weight, m.p.: 151-152
^C. Yield: lL4g, 87%. NMR (DMSO) 5 8.75 (s, IH), 8.51 (s, IH), 8.21 (d, IH), 7.85
(d, IH), 7.65 (d, IH), 7.55 (m, 2H), 7.49 (dd, IH), 7.35 (dd, IH), 6.95 (d, IH), 6.38 (s,

15 IH), 4,26 (dd, 2H), 3.60 (dd, 4H), 2.81 (dd, 2H), 2.55 (dd, 4H), 2.38 (s, 3H), 1.29 (s, 9H).
MS (CI) m/z 528 (M^+1).

The following additional non-limiting examples can be made using the novel process of
the invention:

20

EXAMPLE 2

25 l^[3-tert'butyl-l'p-tolyl-lH'pyrazol-5-ylJ'3-{4-f5-(m^
yljnaphthalen-l-yl} urea:

30 A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-r-butyl- 1 -p-tolylpyrazole (26
mmol), l-amino-4-[5-(morpholin-4-ylmethyl)fur-2-yl]naphthalene (26 mmol),

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diisopropylethylamine ( 25 mmol) and DMSO (75 mL) is heated to 55 - 90^C and held
for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed
with brine (4x50 mL), and dried over MgS04. The solvent is removed under reduced
pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL)
at 0 ^C. The product is collected by filtration and recrystallized from a suitable solvent
such as isopropanol and dried in vacuum to constant weight.

EXAMPLE 3

l-[3-ten-butyl-l~p-tolyl-lH-pyrazol-5-ylJ-3'{4-f6'(morpholin-4^^
yl]naphthalen-l-yl} urea:

A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-/-butyl-l-p-tolylpyrazole (26
mmol), l-amino-4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalene (26 mmol),
diisopropylethylamine ( 25 mmol) and DMSO (75 mL) is heated to 55 - 9(fC and held
for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed
with brine (4x50 mL), and dried over MgS04. The solvent is removed under reduced
pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL)
at 0 ^C. The product is collected by filtration and recrystallized from a suitable solvent
such as isopropanol and dried in vacuum to constant weight.

EXAMPLE 4

l-f3't€rt'butyl'l'P'tolyl-lH-pyrazol-5-ylJ-3'(4-{6'f(^^
methoxypropyl)methylamino]pyridin-3--yl}naphthalen-l-yl)urea

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O

o

A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-/-butyl-l-p-tolylpyrazole (26
5 mmol), l-amino-4-{6-[(3-methoxypropyl)methylamino]pyridin-3-yl}naphthalene (26
mmol), diisopropylethylamine ( 25 mmol) and DMSO (75 mL) is heated to 55 - 90^C
and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer
is washed with brine (4x50 mL), and dried over MgS04. The solvent is removed under
reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile
10 (50 mL) at 0 The product is collected by filtration and recrystallized from a suitable
solvent such as isopropanol and dried in vacuum to constant weight.

20 A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3 -/-butyl- 1-p-tolylpyrazole (26
mmol), l-amino-4-(3-pyridin-4-ylpropoxy)naphthalene (26 mmol),
diisopropylethylamine ( 25 mmol) and DMSO (75 mL) is heated to 55 - 90^C and held
for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed
with brine (4x50 mL), and dried over MgS04, The solvent is removed under reduced

25 pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL)

EXAMPLE 5

15

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at 0 C. The product is collected by filtration and recrystallized from a suitable solvent
such as isopropanol and dried in vacuum to constant weight.

EXAMPLE 6

5

l'[3'tert-butyl-l-(2'methylpyridin'5-yl)'lH'pyrazol'5-yl]-3-[4'(p^

m eth oxy) naphth alen -l~yl ]-urea

10

A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-^-butyl-l-(2-methylpyridin-5-
yl)pyrazole (26 mmol), l-amino-4-(pyridin-4-ylmethoxy)naphthalene (26 mmol),
diisopropylethylamine ( 25 mmol) and DMSO (75 mL) is heated to 55 - 90^C and held
for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed
15 with brine (4x50 mL), and dried over MgS04. The solvent is removed under reduced
pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL)
at 0 *^C. The product is collected by filtration and recrystallized from a suitable solvent
such as isopropanol and dried in vacuum to constant weight.

20

EXAMPLE 7

l'[3-tert-butyl'l-p'tolyUlH-pyrazoU5''yl]-3'[4-(2-pyridin-4'yl'
ethenyl)naphthalen-l-yl]~urea

25

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A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-r-butyl-l-p-tolylpyrazole (26
mmol), l-amino-4-(2-pyridin-4-yl-ethenyl)naphthalene (26 mmol),
diisopropylethylamine (3.2 g, 25 mmol) and DMSO (75 mL) is heated to 55 - 90^C and
held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is
washed with brine (4x50 mL), and dried over MgS04. The solvent is removed under
reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile
(50 mL) at 0 ^C. The product is collected by filtration and recrystallized from a suitable
solvent such as isopropanol and dried in vacuum to constant weight.

EXAMPLE 8

l-(5-tert-Butyl-2-methyphenyl)-3'[4'(6'morpholin~4-ylmethyl-pyrid^

naphth al en -l-ylju rea:

A solution of 5-^-butyl-2-methyl-l-(2,2,2-trichloroethoxycarbonyl)aminobenzene (26
mmol), l-amino-4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalene (26 mmol),
diisopropylethylamine (3.2 g, 25 mmol) and DMSO (75 mL) is heated to 55 - 60 and
held for L5 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is
washed with brine (4x50 mL), and dried over MgS04. The solvent is removed under
reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile
(50 mL) at 0 ^C. The product is collected by filtration and recrystallized from a suitable
solvent such as isopropanol and dried in vacuum to constant weight.

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What is Claimed is:

1.

A process for producing a compound of the formula (I):

Ar

H

H

(I)

wherein:

Ari is a heterocyclic group selected from the group consisting of phenyl, pyridine,
pyridone, pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and
thiophene;

wherein Ari is optionally substituted by one or more Ri, R2 or R3;

phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline,
tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being
optionally substituted with one to three R2 groups;

L, a linking group, is:

Ci-10 saturated or unsaturated branched or unbranched carbon chain;
wherein one or more methylene groups are optionally independently replaced by
0,N or S; and

wherein said linking group is optionally substituted with 0-2 0x0 groups and one
or more C1-4 branched or unbranched alkyl optionally substituted by one or more halogen
atoms;

or L is a cyclic group which is:

a) a C5-8 cycloalkyl or cycloalkenyl optionally substituted with 1-2 0x0 groups, 1-3 Ci_4
branched or unbranched alkyl, C1.4 alkoxy or C1.4 alkylamino chains;

b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine, pyrimidine, pyridinone,
dihydropyridinone, maleimide, dihydromaleimide, piperdine, piperazine or pyrazine each

Av2 is:

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being optionally independently substituted with 1-3 Ci .4 branched or unbranched alkyl,
Ci-4alkoxy, hydroxy, cyano, mono- or di-(Ci.3 alkyl)amino, C1.6 alkyl-S(0)q, or halogen;

wherein said cyclic group is optionally attached to a C1-4 saturated or unsaturated
branched or unbranched carbon chain wherein said carbon chain is in turn covalently
attached to Q , said carbon chain is optionally partially or fully halogenated and wherein
one or more methylene groups are optionally replaced by O, NH, S(0), S(0)2 or S,
wherein said methylene groups are further optionally independently substituted with 1-2
0x0 groups and one or more Ci_4 branched or unbranched alkyl optionally substituted by
one or more halogen atoms;

Q is selected from the group consisting of:

a) phenyl, naphthyl, pyridine, pyrimidine, pyridazine, imidazole, benzimidazole, furan,
thiophene, pyran, naphthyridine, oxazo[4,5-6]pyridine and imidazo[4,5-6]pyridine,
which are optionally substituted with one to three groups selected from the group
consisting of halogen, Cue alkyl, Ci-6 alkoxy, hydroxy, mono- or di-(Ci.3 alkyl)amino,
Ci-6 alkyl-S(0)m and phenylamino wherein the phenyl ring is optionally substituted
with one to two groups selected from the group consisting of halogen, Ci,6 alkyl and
C1.6 alkoxy;

b) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxane,
morpholine, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone,
piperidine, piperidinone, tetrahydropyrimidone, cyclohexanone, cyclohexanol,
pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone,
tetramethylene sulfide, tetramethylene sulfoxide and tetramethylene sulfone which
are optionally substituted with one to three groups selected from the group consisting
of Ci-6 alkyl, Ci-6 alkoxy, hydroxy, mono- or di-(Ci_3 alky l)amino-C 1.3 alkyl,
phenylamino-Ci-3 alkyl and C1.3 alkoxy-Ci_3 alkyl;

c) C1.6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently
bonded to groups selected from the group consisting of C1.3 alkyl and C1.5 alkoxyalkyl
and phenyl wherein the phenyl ring is optionally substituted with one to two groups
selected from the group consisting of halogen. Cue alkoxy, hydroxy or mono- or di-

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(C1.3 alkyl)amino, Ci-e alkyl-S(0)r and phenyl-S(0)t, wherein the phenyl ring is
optionally substituted with one to two groups consisting of halogen, Ci_6 alkoxy,
hydroxy and mono- or di-(Ci-3 alkyl)amino;

Ri is selected from the group consisting of:

a) C3-10 branched or unbranched alkyl, which may optionally be partially or fully
halogenated, and optionally substituted with one to three phenyl, naphthyl or
heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl,
pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and
isothiazolyl; each such phenyl, naphthyl or heterocycle selected from the group
hereinabove described, being substituted with 0 to 5 groups selected from the group
consisting of halogen, C\.6 branched or unbranched alkyl which is optionally partially
or fully halogenated, Cs-g cycloalkyl, C5-8 cycloalkenyl, hydroxy, cyano, C1.3 alkyloxy
which is optionally partially or fiilly halogenated, NH2C(0) and
di(Ci.3)alkylaminocarbonyl;

b) C3.7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl,
cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and
bicycloheptanyl, which are optionally partially or fully halogenated and optionally
substituted with one to three C1-3 alkyl groups, or an analog of such cycloalkyl group
wherein one to three ring methylene groups are replaced by groups independently
selected from O, S, CHOH, >C=0, >C=S and NH;

c) C3-10 branched alkenyl which may optionally be partially or fully halogenated, and
which optionally be substituted with one to three Cus branched or unbranched alkyl,
phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being
independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl,
pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and
isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted
with 0 to 5 groups selected from halogen, Ci-6 branched or unbranched alkyl which is
optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl,
cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl.

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hydroxy, cyano, C1.3 alkyloxy which is optionally partially or fully halogenated,
NH2C(0) and mono- or di(Ci.3)alkylaminocarbonyl;

d) C5-7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl,
cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and
bicycloheptenyl, wherein such cycloalkenyl group is optionally be substituted with
one to three C1.3 alkyl groups;

e) cyano; and,

f) methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;

R2 is selected from the group consisting of:

a Ci-6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl,
aroyl, C1-4 branched or unbranched alkoxy optionally partially or fully halogenated,
halogen, methoxycarbonyl and phenylsulfonyl;

R3 is selected from the group consisting of:

a) a phenyl, naphthyl or heterocyclic group selected from the group consisting of
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl,
thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl,
indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl,
benzothiofiaranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl,
quinoxalinyl, quinazolinyl, purinyl and indazolyl wherein such phenyl, naphthyl or
heterocyclic group is optionally substituted with one to five groups selected from the
group consisting of a Ci_6 branched or unbranched alkyl, phenyl, naphthyl,
heterocycle selected from the group hereinabove described, Ci,6 branched or
unbranched alkyl which is optionally partially or fiilly halogenated, cyclopropyl,
cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,
bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, halo, hydroxy,
cyano, C1.3 alkyloxy which may optionally be partially or fully halogenated,

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phenyloxy, naphthyloxy, heteraryloxy wherein the heterocychc moiety is selected
from the group hereinabove described, nitro, amino, mono- or di-(C 1.3) alky lamino,
phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is
selected from the group hereinabove described, NH2C(0), a mono- or di-(Ci.3)alkyl
aminocarbonyl, C1.5 alkyl-C(0)-Ci_4 alkyl, amino-Ci-5 alkyl, mono- or di-(Ci.
3)alkylamino-Ci-5 alkyl, amino-S(0)2, di-(Ci-3)alkylamino-S(0)2, R4-Ci.5alkyl, R5-C1-
5 alkoxy, R6-C(0)-Ci.5 alkyl and R7-C1.5 alkyl-NCRg)-;
b) a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl,
indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and
benzocycloheptenyl, or a fused heterocyclyl selected from cyclopentenopyridine,
cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine,
cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine,
cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline,
cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole,
cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole,
cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole,
cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein
the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups
independently selected from phenyl, naphthyl, heterocyclyl selected from the group
consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,
pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C1.6 branched or unbranched
alkyl which is optionally partially or fully halogenated, halo, cyano, C1-3 alkyloxy
which is optionally partially or fully halogenated, phenyloxy, naphthyloxy,
heterocyclyloxy wherein the heterocyclyl moiety is selected from the group
hereinabove described, nitro, amino, mono- or di-(Ci.3)alkylamino, phenylamino,
naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from
the group hereinabove described, NH2C(0), a mono- or di-(Ci.3)alkyl aminocarbonyl,
Ci_4 alkyl-OC(O), Ci_5 alkyl-C(0)-Ci^ branched or unbranched alkyl, an amino-Ci-5
alkyl, mono- or di-(Ci.3)alkylamino-Ci.5 alkyl, R9-C1-5 alkyl, R10-C1-5 alkoxy, Rn -
C(0)-Ci.5 alkyl and R12 -C1.5 alkyl-N(Ri3)-;

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c) cycloalkyl selected from the group consisting of cyclopentanyl, cyclohexanyl,
cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, wherein the
cycloalkyl is optionally partially or fully halogenated and optionally substituted with
one to three C1.3 alkyl groups;

5

d) C5-7 cycloalkenyl, selected from the group consisting of cyclopentenyl, cyclohexenyl,
cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and
bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one
to three C1.3 alkyl groups;

10

e) acetyl, aroyl, alkoxycarbonylalkyl and phenylsulfonyl; and

f) Ci-6 branched or unbranched alkyl optionally partially or fully halogenated;
15 Ri and R2 taken together optionally form a fused phenyl or pyridinyl ring;

each Rg and R13 is independently selected from the group consisting of:
hydrogen and C1-4 branched or unbranched alkyl optionally partially or fully halogenated;

20

each R4, R5, R6, R7, R9, Rio, Rii and R12 is independently selected from the group
consisting of:

morpholine, piperidine, piperazine, imidazole and tetrazole;
25 m is 0, 1 or 2;
r is 0, 1 or 2;
q is 0, 1 or 2;

30

t is 0, 1 or 2; and

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X is O or S;

said process comprising:

reacting of intermediate of formula (II) with intermediate of formula (IV) in the
presence of a suitable base said reaction taking place in a suitable solvent at a suitable
temperature for a reaction time of about 1.5 hours:

Ar.

N
H

X

ORa

.Ar

Q

+

H^N

X

Arj\ /Ar^-

I I
H H

Q

10 (II) (IV) (I)

wherein Ra is a C2-3 halocarbon, Ari, Ar2, X, L and Q are as defined hereinabove; to
produce a compound of formula (I).

15 2. The process according to claim 1 wherein

Ra is 2,2,2-trichloroethyl;

the organic solvent is a polar non-protic solvent selected from the group
consisting of NMP, acetonitrile, DMF, DMAC and DMSO;

the base is selected from the group consisting of triethylamine,
20 diisopropylethylamine, N-methylpyrrolidine, DBU, DMAP, N-methylmorpholine,
pyridine, methyl pyridine and an inorganic base;
the temperature is about 55-60^C;

Ar2 is selected from the group consisting of naphthyl, tetrahydronaphthyl, indanyl
25 and indenyl, and

Xis O.

3 . The process according to claim 2 wherein
Ar2 is naphthyl;

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the polar non-protic organic solvent is selected from the group consisting of
NMP and DMSO; and

the base is selected from the group consisting of diisopropylethylamine and N-
methy Ipy rrolidine .

4. The process according to claim 3 wherein
Ari is thiophene or pyrazole;
Ar2 is 1-naphthyl;

L is Ci.6 saturated or unsaturated branched or unbranched carbon chain wherein
one or more methylene groups are optionally independently replaced by
0,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups
and one or more C1-4 branched or unbranched alkyl optionally substituted by one or more
halogen atoms;

or L is cyclopentenyl, cyclohexenyl or cycloheptenyl each optionally substituted with an
0x0 group or 1-3 C1.4 branched or unbranched alkyl, Ci-4alkoxy or Ci_4alkylamino; or L
is phenyl, pyridine, furan or thiophene each being optionally independently substituted
with 1-3 Ci_4 branched or unbranched alkyl, Ci^alkoxy, hydroxy, cyano, mono- or di-
(Ci_3 alkyl)amino, Ci-e alkyl-S(0)q or halogen;

wherein said cyclic group is optionally attached to a C 1-4 saturated or unsaturated
branched or unbranched carbon chain wherein said carbon chain is in tum covalently
attached to Q , said carbon chain is optionally partially or fully halogenated and wherein
one or more methylene groups are optionally replaced by O, NH, S(0), S(0)2 or S,
wherein said methylene groups are further optionally independently substituted with 1-2
0x0 groups and one or more C1-4 branched or unbranched alkyl optionally substituted by
one or more halogen atoms;

Ri is Cs^alkyl branched or unbranched, cyclopropyl or cyclohexanyl optionally
partially or fully halogenated and optionally substituted with one to three C1.3 alkyl
groups;

R3 is selected from the group consisting of Ci^alkyl branched or unbranched
optionally partially or fully halogenated;

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cyclopentanyl optionally partially or fully halogenated and optionally substituted
with one to three C1.3 alkyl groups;

phenyl, pyridinyl each being optionally substituted with one to five groups
selected from the group consisting of a Ci-6 branched or unbranched alkyl, phenyl,
naphthyl, pyridinyl, C1.6 branched or unbranched alkyl which is optionally partially or
fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1.5 alkyl, naphthyl C1.5 alkyl,
halo, hydroxy, cyano, Ci_3 alkyloxy which may optionally be partially or fully
halogenated, phenyloxy, naphthyloxy, pyridinyloxy, nitro, amino, mono- or di-(Ci.
3)alkylamino, phenylamino, naphthylamino, pyridinylamino, NH2C(0), a mono- or di-
(Ci-3)alkyl aminocarbonyl, C1-5 alkyl-C(0)-Ci^ alkyl, amino-Ci_5 alkyl, mono- or di-(Ci.
3)alkylamino-Ci.5 alkyl, amino-S(0)2, di-(Ci.3)alkylamino-S(0)2, R4-Ci.5alkyl, Rs-Ci-s
alkoxy, R6-C(0)-Ci.5 alkyl and R7-C1-5 alkyl-NCRg)-;
and R3 is alkoxy carbonylalkyl;

5. The process according to claim 4
wherein Ari is pyrazole.

6. The process according to claim 5 wherein L is C1-5 saturated carbon chain wherein
one or more methylene groups are optionally independently replaced by 0,N or S; and
wherein said linking group is optionally substituted with 0-2 0x0 groups and one or more
Ci^ branched or unbranched alkyl optionally substituted by one or more halogen atoms.

7. The process according to claim 5 wherein

L is propoxy, ethoxy, methoxy, methyl, propyl, C3-5 acetylene or methylamino each
optionally substituted with 0-2 0x0 groups and one or more Ci^ branched or unbranched
alkyl optionally substituted by one or more halogen atoms; and
Q is morpholine.

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7.

The process according to claim 6 wherein L is propoxy, ethoxy or methoxy.

8. The process according to claim 7 wherein L is ethoxy, the base is
diisopropylethylamine and the polar non-protic organic solvent is DMSO.

9.

A process of producing an intermediate compound of the formula(II)

X

Ar

N
H

ORa

(11)

comprising:

reacting an aminoheterocycle NH2- Ari with with a formate RaOC(X)Ha, in a suitable
solvent in the presence of a suitable base at about 0 to lOO^C for about 0,5 to 24 hours,
wherein

Ra represents C2-3 halocarbon, and Ha represents halogen, X and Ari are as defined in
claim 1, to produce carbamate of the formula (II).

10. The process according to claim 9 wherein
Ra is 2,2,2-trichloroethyl,
Ha is chloro,
Xis O,

the solvent is THF or ethyl acetate,

the base is selected fi-om the group consisting diisopropylethylamine, N-
methylpyrrolidine and NaOH;

the temperature is about 5 to 15^C; and
the time is about 3 hours.

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10

11. A carbamate compound of fomiula:

X

Ar

^ N OCHXCL
H ^ ^

5 wherein Ari is thiophene or pyrazole and X is O.

12. The carbamate compound according to claim 1 1
wherein Ari is l-tolyl-3-^-butyl-pyrazole-5-yl.

13. A process for producing an intermediate compound of the formula (III)

15 ^ (III)

comprising:

reacting a Z-Ar2-MH compound with a Y-J-Q moiety in a polar non-protic organic
solvent at a temperature of about 50-100*^C to produce the intermediate with formula
20 (III);

wherein Z is a nitro or nitroso group, M is O, S, or NH, Y is a leaving group, M-J
constitutes L; and wherein Ar2, L and Q are as defined in claim 1.

14. The process according to claim 13 wherein the solvent is selected from the group
25 consisting of acetonitrile, DMF, DMAC, DMSO and NMP and the temperature is about
75-95^C.

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An intermediate compound of the formula(III):

(III)

wherein Z is nitro or nitroso and wherein
Ax2 is 1 -naphthyl,

L is propoxy, ethoxy, methoxy, methyl, propyl, C3.5 acetylene or methylamino,
and Q is morpholine.

16. A process of producing an intermediate compound of formula (IV):

comprising:

reducing compound of formula (III) by catalytic hydrogenation with a Pd/C catalyst
under about 30 psi for about 1-24 h:

wherein Z,Ar2,L and Q are as defined above in claim 13, to produce the intermediate
of formula (IV).

2

(IV)

(HI),

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